Biologically active compounds which are peptide or protein in nature have proved to be difficult to administer by the oral route to patients in need of treatment. The active material may be degraded by chemical or enzymatic agents in the gut such as the peptidases, strong acid, oxidizing agents and the like. Other factors may be physical instability, denaturation, surface adsorption, aggregation of proteins or precipitation in the gut.
Workers have sought a solution for this art problem in many ways, such as by means of liposome delivery (U.S. Pat. No. 4,356,167), lipid coating (U.S. Pat. No. 4,849,227, WO87/05505), use of peptidase inhibitors (U.S. Pat. No. 4,579,730), prodrugs, targeted microspheres (WO88/01213), coaccervate systems (U.S. Pat. No. 4,849,405) or, lately, emulsion formulations.
The use of oil/water emulsions for the oral delivery of peptides has received particular attention. Earlier work is summarized by M. Shichiri et al. (Acta diabet. lat. 15, 175 (1978)) and W. A. Ritschel (Meth. Find. Exp. Clin. Pharmacol. 13, 205 (1991)). The art terms and disclosures of the latter publication are incorporated herein by reference.
Y. W. Cho et al (PCT patent application WO 90/03164) discloses the use of oral proteinaceous compositions comprising oil/water emulsions which form chylomicra or deliver chylomicra to absorption sites in the gastrointestinal tracts. Cho discloses on page 9, line 23-29 that the hydrophilic phase (aqueous phase) may contain ethanol. In fact, the preferred embodiments, such as in the examples all contain a substantial quantity of ethanol in the aqueous layer of the emulsion. Also the emulsion is preferably adsorbed on particles before encapsulation (Example 3).
The prior art products have drawbacks in that oil/water emulsions are known in the art to have stability problems. The Cho products, when prepared as described in the PCT publication, have a disagreeable oily appearance which is not pharmaceutically elegant. Ethanol is also a well-known denaturant of many proteinaceous medicaments. The microfluidization process described by Cho also can denature the proteinaceous material due to heat and shear involved in the process.